Combined inhibition of EZH2 and the autotaxin-LPA-LPA2 axis exerts synergistic antitumor effects on colon cancer cells

Autotaxin (ATX), also known as ENPP2, is the key enzyme in lysophosphatidic acid (LPA) production. LPA acts on its receptors on the cell membrane to promote cell proliferation and migration, and thus, the ATX-LPA axis plays a critical role in tumorigenesis. Clinical data analysis indicated that in colon cancer, there is a strong negative correlation between the expression of ATX and EZH2, the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2). Here, we demonstrated that ATX expression was epigenetically silenced by PRC2, which was recruited by MTF2 and catalyzed H3K27me3 modification in the ATX promoter region. EZH2 inhibition is a promising strategy for cancer treatment, and ATX expression is induced in colon cancer cells by EZH2 inhibitors. With both EZH2 and ATX as targets, their combined inhibition exerted synergistic antitumor effects on colon cancer cells. In addition, LPA receptor 2 (LPA2) deficiency significantly enhanced the sensitivity to EZH2 inhibitors in colon cancer cells. In summary, our study identified ATX as a novel PRC2 target gene and found that cotargeting EZH2 and the ATX-LPA-LPA2 axis may be a potential combination therapy strategy for colon cancer.